Dapagliflozin Modulates the Fecal Microbiota in a Type 2 Diabetic Rat Model.

Background: The gut microbiota is recognized as a major modulator of metabolic disorders such as type 2 diabetes. Dapagliflozin, sodium glucose cotransporter 2 inhibitors (SGLT2i), enhances renal glucose excretion, and lowers blood glucose levels. The study aimed to determine the effects of dapagliflozin on fecal microbiota in a type 2 diabetic rat model. Methods: Four-week-old male Sprague Dawley rats (n = 24) were fed a high-fat diet (HFD) for 8 weeks and then given a single dose of STZ injection (30 mg/kg, i.p). They were randomly divided into three groups (n = 8). Each group received intragastric infusion of normal saline (2 ml, 0.9%) or metformin (215.15 mg/kg/day) or dapagliflozin (1 mg/kg/day) for 4 weeks. Blood glucose levels and plasma insulin levels were detected during intragastric glucose tolerance. Fecal samples were collected to access microbiome by 16S ribosomal RNA gene sequencing. Results: Dapagliflozin significantly decreased fasting and postprandial blood glucose levels as metformin in type 2 diabetic rats (P < 0.001). Enterotype was composed of Ruminococcaceae after treatment of dapagliflozin, whereas Ruminococcaceae and Muribaculaceae were the main enterotypes following metformin treatment. Dapagliflozin did not increase the abundance of beneficial bacteria including Lactobacillaceae and Bifidobacteriaceae. However, these were increased in the metformin group. It is surprising to find that Proteobacteria (especially Desulfovibrionaceae) were enriched in the dapagliflozin group. Conclusion: Dapagliflozin and metformin exerted complementary effects on the main beneficial bacteria. A combination of these two drugs might be beneficial to improve the structure of fecal microbiota in the treatment of type 2 diabetes.

Secretion of Gut Hormones and Expression of Sweet Taste Receptors and Glucose Transporters in a Rat Model of Obesity.

OBJECTIVES: This study was undertaken to compare gut hormone secretion between high-fat-fed and control rats, and to examine the corresponding changes in the expression of sweet taste receptors and glucose transporters in the small intestine and hypothalamus. METHODS: Four-week-old male Sprague Dawley rats were fed a standard or high-fat diet for 8 weeks (10 in each group), followed by an oral glucose tolerance test (50% glucose solution, 2 g/kg). Blood was sampled for glucose, insulin, glucagon-like peptide-1 (GLP-1) and polypeptide YY (PYY) assays. One week later, small intestinal and hypothalamic tissue were analyzed for sweet taste receptor and glucose transporter expression by real-time PCR. RESULTS: After oral glucose, plasma GLP-1 concentrations were higher in high-fat-fed than standard-fat-fed rats (group × time interaction, p < 0.01) with significant differences at t = 15 min (p < 0.01) and 30 min (p < 0.05). Plasma PYY concentrations were lower in high-fat-fed than control rats at t = 0, 15 min (p < 0.05, respectively) and 120 min (p < 0.01). There were no differences in the expression of sweet taste receptors or glucose transporters between high-fat-fed and control rats in the duodenum, ileum, or hypothalamus. CONCLUSIONS: Changes in GLP-1 and PYY secretion after a high-fat diet appear unrelated to any changes in the expression of sweet taste receptors or glucose transporters. Impaired PYY secretion with high-fat feeding suggests that PYY analogues may provide a potential therapy in the treatment of obesity.